- Open Access
Pidotimod: the past and the present
© Zuccotti and Mameli; licensee BioMed Central Ltd. 2013
- Received: 19 July 2013
- Accepted: 3 December 2013
- Published: 6 December 2013
At the end of 1990s, acute respiratory tract infections (ARTIs) were called the 'forgotten pandemic’, with a clear dichotomy between developing and industrialised countries in mortality and morbidity, the main outcomes associated with ARTIs. This definition still applies 20 years later, when the introduction of new and safe antibiotics and vaccines has certainly contributed to controlling the most life-threatening ARTIs, but has not had a major impact on viral ARTIs in paediatric age. One functional approach to preventing and treating ARTIs is non-specifically increasing the immune response or enhancing the children’s innate defence mechanisms. Different kinds of biologically active substances – called immunostimulants – of natural and synthetic origins and with different mechanisms of action have been introduced in some countries for the prevention of ARTIs in children. Recently, research focused on one of these compounds, Pidotimod, has attempted to better clarify and define its mechanisms of action both in vitro and in vivo. In this paper, we critically examine the most recent findings on Pidotimod. Certainly the improvement of research methodology in the last 20 years and the acquired knowledge in various fields of clinical immunology should be the starting point for research on Pidotimod. Preclinical research will be essential to better understand the mechanisms of action of this compound. However, in vivo studies, especially randomised control trials, will be necessary to establish the real efficacy of Pidotimod in the prevention of ARTIs in paediatric age.
- Recurrent respiratory infections
At the end of 1990s, acute respiratory tract infections (ARTIs) were called the 'forgotten pandemic’, with a clear dichotomy between developing and industrialised countries in mortality and morbidity, the main outcomes associated with ARTIs . This definition still applies 20 years later, when the introduction of new and safe antibiotics and vaccines has certainly contributed to controlling the most life-threatening ARTIs, but have not had a major impact on viral ARTIs. Viruses are the main agents responsible for ARTIs during the paediatric age and the high number of circulating virus and the different viral sub-types result in a higher probability of experiencing frequent ARTIs during childhood . These epidemiological features besides the well-known immaturity of the immune system during the first years of life and the exposure to risk factors (air pollution, parental tobacco smoke, daycare attendance) are mainly responsible of the recurrence of ARTIs, and contribute to the incidence of recurrent respiratory infections especially in the first 6 years of life [3–5].
Today, the socio-economical burden of ARTIs remains high in industrialised countries. The pharmacological cost of symptomatic drugs, antibiotics, the search for assistance by a general practitioner, hospitalisation, as well as specialist referral contribute to healthcare expenses [6–8]. Moreover, indirect costs such as parental absences from work and loss of productivity should not be neglected . In consideration of current epidemiological and socio-economical data, there is a need for alternative approaches to the most well-studied and known therapies.
One functional approach to preventing and treating ARTIs is non-specifically increasing the immune response or enhancing the child’s innate defence mechanisms. Different kinds of biologically active substances – called immunostimulants – of natural and synthetic origins and with different mechanisms of action have been introduced in some countries for the prevention of ARTIs in children [10–13]. Concerning the real mechanisms of action, efficacy and safety issues have discouraged their use in different settings, in some European countries as well as in the USA. Certainly most of studies on immunostimulants were conducted many years ago and the methodological bias reported was not entirely insignificant. In our opinion, a new research input is now essential to overcome this bias, to provide new efficacy and safety data on the role of Pidotimod in preventing ARTIs in childhood.
New evidences on mechanisms of action of Pidotimod
Recently, research focused on one of these compounds, Pidotimod, has attempted to better clarify and define its mechanism of action both in vitro and in vivo. Pidotimod (3-L-pyroglutamyl-L-thiaziolidine-4carboxylic acid) is a synthetic dipeptide molecule with immunomodulatory properties . It is a highly purified molecule with high reproducibility among batches. It is rapidly absorbed by the gastrointestinal tract, with a bioavailability of 45% not influenced by food and is eliminated unmodified via renal excretory mechanisms . The safety profile of Pidotimod is good; no serious adverse events were reported in human studies except for one case of suspected Henoch-Schönlein purpura . However, no other association with autoimmune diseases have been reported so far.
In vitro studies in both animal and human specimens have shown that Pidotimod has an immunomodulatory activity on both innate and adaptive immune responses. Pidotimod induces dendritic cell (DC) maturation, upregulates the expression of HLA-DR and co-stimulatory molecules CD83 and CD86, stimulates DCs to release pro-inflammatory molecules, driving T cell proliferation and differentiation towards a Th1 phenotype, enhances natural killer cell functions, inhibits thymocyte apoptosis, and promotes phagocytosis [17–19]. More recently, Carta et al. showed that Pidotimod induced in vitro cellular changes that are potentially useful in enhancing the capability of the host to fight respiratory infections . Through different effects on extracellular-signal-regulated kinase (ERK1/2) and nuclear factor-kappa B (NF-kB), Pidotimod increases the expression of toll-like receptor 2 proteins (surface molecules involved in the initiation of the innate response to infectious stimuli). The lack of effect on intercellular adhesion molecule (ICAM)-1 expression, the receptor for rhinovirus, and on interleukin (IL)-8 release, the potent chemotactic factor for neutrophils (usually present at sites of infection), may represent protective functions from infections. The authors concluded that Pidotimod seemed to modulate airway epithelial cell functions involved in host-virus interactions, possibly through NF-kB activation.
Studies performed using in vivo and in vitro (animal and cellular) experimental model systems are essential for identifying the biological mechanisms of action of Pidotimod, based on the assumption that these biological models have known ability to predict human responses. In spite of the encouraging results coming from in vitro studies, to date, in vitro systems do not predict all aspects of the mechanisms of action of a drug. Thus, a combination of in vitro and human studies is required for better characterisation of the efficacy of Pidotimod.
A recent example of bridging the gap between preclinical and clinical research was provided by Zuccotti et al. in a study conducted on children with Down syndrome, a population who frequently experiences ARTIs . The authors randomised a cohort of subjects to receive Pidotimod orally or placebo and analysed immune parameters before and after the injection of seasonal 2011–2012 virosomal adjuvanted influenza vaccine. They found that the use of Pidotimod was associated with the upregulation of a number of genes involved in the activation of innate immune responses and in antimicrobial activity. Moreover, the ratio of flu-specific immunoglobulin G1/G3 (IgG1/IgG3) was skewed in Pidotimod-treated individuals, suggesting a preferential activation of complement-dependent effector mechanisms. Although preliminary, these data suggest that Pidotimod can potentiate the beneficial effect of immunisation, possibly resulting in a stronger activity of both innate and adaptive immune responses.
Up to now, clinical research on Pidotimod has mainly focused on the prevention and treatment of ARTIs in childhood. Studies conducted in the 1990s have shown that this compound seems to have a beneficial effect in children, reducing the number of ARTI, the number of days of fever, and the severity of the signs and symptoms of acute episodes [22–27]. A significant reduction in use of antibiotics, antipyretic drugs, and symptomatic drugs, and absence from school/nursery school and caregiver absenteeism was also observed [22–27]. More recently, a randomised trial has suggested that Pidotimod therapy is a reliable, simple, and safe approach to treat children with recurrent respiratory infections and it can reduce the frequency of such infections as a result of improvement of the ciliary respiratory epithelium .
A Cochrane meta-analysis that included all comparative randomised controlled trials that enrolled participants less than 18 years of age showed that immunostimulants reduced the incidence of ARTIs by 40% on average in susceptible children . However, some bias such as the heterogeneity of subjects recruited in trials in terms of sample size, age, confounding factors (eg, concomitant asthma or allergy, number of siblings, smokers at home, seasons during the study, time and timing of attendance at daycare centre), duration of the intervention, and misused statistical tests limits the strength of conclusions of the majority of studies.
Certainly the improvement of research methodology in the last 20 years and the acquired knowledge in various fields of clinical immunology should be the starting point for research on Pidotimod. Preclinical research will continue to be essential to better understand the mechanisms of action of this compound. However, in vivo studies, especially randomised double-blind controlled trials, are necessary to establish the role of Pidotimod in preventing ARTIs in paediatric age.
- Acute respiratory infections: the forgotten pandemic. Bull World Health Organ. 1998, 76: 101-103.http://www.ncbi.nlm.nih.gov/pubmed/9615503,
- Griffin MR, Walker FJ, Iwane MK, Weinberg GA, Staat MA, Erdman DD, New Vaccine Surveillance Network Study Group: Epidemiology of respiratory infections in young children: insights from the new vaccine surveillance network. Pediatr Infect Dis J. 2004, 23: 188-192. 10.1097/01.inf.0000144660.53024.64.View ArticleGoogle Scholar
- Karevold G, Kvestad E, Nafstad P, Kvaerner KJ: Respiratory infections in schoolchildren: co-morbidity and risk factors. Arch Dis Child. 2006, 91: 391-395. 10.1136/adc.2005.083881.PubMed CentralView ArticlePubMedGoogle Scholar
- Forssel G, Hakansson A, Mansson NO: Risk factors for respiratory tract infections in children aged 2–5 years. Scand J Prim Health Care. 2001, 19: 122-125. 10.1080/028134301750235376.View ArticleGoogle Scholar
- De Martino M, Ballotti S: The child with recurrent respiratory infections: normal or not?. Pediatr Allergy Immunol. 2007, 18: 13-18. 10.1111/j.1399-3038.2007.00625.x.View ArticlePubMedGoogle Scholar
- van de Pol AC, van der Gugten AC, van der Ent CK, Schilder AG, Benthem EM, Smit HA, Stellato RK, de Wit NJ, Damoiseaux RA: Referrals for recurrent respiratory tract infections including otitis media in young children. Int J Pediatr Otorhinolaryngol. 2013, 77: 906-910. 10.1016/j.ijporl.2013.03.003.View ArticlePubMedGoogle Scholar
- Bellanti JA: Recurrent respiratory tract infections in paediatric patients. Drugs. 1997, 54: 1-4.View ArticlePubMedGoogle Scholar
- Acute respiratory infections: the forgotten pandemic. Communiqué from the international conference on acute respiratory infections, held in Canberra, Australia, 7–10 July 1997. Int J Tuberc Lung Dis. 1998, 2: 2-4.http://www.ncbi.nlm.nih.gov/pubmed/?term=Acute+respiratory+infections%3A+the+forgotten+pandemic.+Communiqu%C3%A9+from+the,
- McCutcheon H, Fitzgerald M: The public health problem of acute respiratory illness in childcare. J Clin Nurs. 2001, 10: 305-310. 10.1046/j.1365-2702.2001.00486.x.View ArticlePubMedGoogle Scholar
- Schaad UB: OM-85 BV, an immunostimulant in pediatric recurrent respiratory tract infections: a systematic review. World J Pediatr. 2010, 6: 5-12. 10.1007/s12519-010-0001-x.View ArticlePubMedGoogle Scholar
- Rozy A, Chorostowska-Wynimko J: Bacterial immunostimulants–mechanism of action and clinical application in respiratory diseases. Pneumonol Alergol Pol. 2008, 76: 353-359.PubMedGoogle Scholar
- Ounis I: Determination of the antiinfectious activity of RU 41740 (Biostim) as an example of an immunomodulator. Adv Exp Med Biol. 1992, 319: 165-174. 10.1007/978-1-4615-3434-1_17.View ArticlePubMedGoogle Scholar
- Fiocchi A, Terracciano L, Martelli A, Bernardo L, Calcinai E, Marcassa S: Ribosome-component immune modulation of respiratory tract infections in children. Allergy Asthma Proc. 2009, 30 (Suppl 1): S21-31.View ArticlePubMedGoogle Scholar
- Riboldi P, Gerosa M, Meroni PL: Pidotimod: a reappraisal. Int J Immunopathol Pharmacol. 2009, 22: 255-262.PubMedGoogle Scholar
- D’Angelo L, De Ponti F, Crema F, Caravaggi M, Crema A: Effect of food on the bioavailability of Pidotimod in healthy volunteers. Arzneimittelforschung. 1994, 44: 1473-1475.PubMedGoogle Scholar
- Cantarini L, Brogna A, Fioravanti A, Galeazzi M: Henoch-Schönlein purpura associated with Pidotimod therapy. Clin Exp Rheumatol. 2008, 26: S152-PubMedGoogle Scholar
- Auteri A, Pasqui AL, Bruni F, Saletti M, Di Renzo M, Bova G: Effect of Pidotimod, a new immunostimulating agent, on some aspects of immune response. In vitro study. Pharmacol Res. 1992, 26: 196-197.View ArticlePubMedGoogle Scholar
- Migliorati G, D’Adamio L, Coppi G, Nicoletti I, Riccardi C: Pidotimod stimulates natural killer cell activity and inhibits thymocyte cell death. Immunopharmacol Immunotoxicol. 1992, 14: 737-748. 10.3109/08923979209009231.View ArticlePubMedGoogle Scholar
- Migliorati G, Nicoletti I, Riccardi C: Immunomodulating activity of Pidotimod. Arzneimittelforschung. 1994, 44: 1421-1424.PubMedGoogle Scholar
- Carta S, Silvestri M, Rossi GA: Modulation of airway epithelial cell functions by Pidotimod: NF-kB cytoplasmatic expression and its nuclear translocation are associated with an increased TLR-2 expression. Ital J Pediatr. 2013, 39: 29-10.1186/1824-7288-39-29.PubMed CentralView ArticlePubMedGoogle Scholar
- Zuccotti GV, Mameli C, Trabattoni D, Beretta S, Biasin M, Guazzarotti L, Clerici M: Immunomodulating activity of Pidotimod in children with Down syndrome. J Biol Regul Homeost Agents. 2013, 27: 253-258.PubMedGoogle Scholar
- Burgio GR, Marseglia GL, Severi F, De Benedetti F, Masarone M, Ottolenghi A, Pagliano L, Serra U, Nespoli L: Immunoactivation by Pidotimod in children with recurrent respiratory infections. Arzneimittelforschung. 1994, 44: 1525-1529.PubMedGoogle Scholar
- Motta G, De Campora E, De Vita C, Esposito S, Galletti C, Incutti V, Mallardi V, Motta S, Pucci V, Salonna F: Immunoactivity of Pidotimod against episodes of recurrent tonsillitis in childhood. Arzneimittelforschung. 1994, 44: 1521-1524.PubMedGoogle Scholar
- Careddu P, Mei V, Venturoli V, Corsini A: Pidotimod in the treatment of recurrent respiratory infections in paediatric patients. Arzneimittelforschung. 1994, 44: 1485-1489.PubMedGoogle Scholar
- Caramia G, Clemente E, Solli R, Mei V, Cera R, Carnelli V, Venturoli V, Corsini A: Efficacy and safety of Pidotimod in the treatment of recurrent respiratory infections in children. Arzneimittelforschung. 1994, 44: 1480-1484.PubMedGoogle Scholar
- Passali D, Calearo C, Conticello S: Pidotimod in the management of recurrent pharyngotonsillar infections in childhood. Arzneimittelforschung. 1994, 44: 1511-1516.PubMedGoogle Scholar
- La Mantia I, Grillo C, Mattina T, Zaccone P, Xiang M, Di Mauro M, Meroni PL, Nicoletti F: Prophylaxis with the novel immunomodulator Pidotimod reduces the frequency and severity of upper respiratory tract infections in children with Down’s syndrome. J Chemother. 1999, 11: 126-130.View ArticlePubMedGoogle Scholar
- Aivazis V, Hatzimichail A, Papachristou A, Valeri R, Iuga-Donca G: Clinical evaluation and changes of the respiratory epithelium function after administration of Pidotimod in Greek children with recurrent respiratory tract infections. Minerva Pediatr. 2002, 54: 315-319.PubMedGoogle Scholar
- Del-Rio-Navarro BE, Espinosa Rosales F, Flenady V, Sienra-Monge JJ: Immunostimulants for preventing respiratory tract infection in children. Cochrane Database Syst Rev. 2006, 4: CD004974-PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.